Regenerating the optic nerve was long considered impossible. But over the last 20 years, advances in the field have instilled confidence in many researchers—including Larry Benowitz, PhD, Professor of Ophthalmology and Neurosurgery at Harvard Medical School—that regenerating the optic nerve is not only possible, but also could transform the clinical practice of ophthalmology in as few as 15 years.
A leader in the field of optic nerve regeneration, Dr. Benowitz has dedicated nearly 40 years of his basic and translational research career at Boston Children’s Hospital to studying how the brain rewires itself after injury.
Inflammation Stimulates Regeneration
He initially focused on the regeneration of the optic nerve in lower vertebrates like fish. Then he began studying retinal ganglion cells after British Scientist Martin Berry discovered that a peripheral nerve graft implanted into the back of the eye could stimulate nerve cells in the retina.
Among Dr. Benowtiz’s early findings was that inflammation in the eye caused some retinal ganglion cells to regenerate. Later, he found that inflammatory cells produce a growth factor called oncomodulin.
“Around the time our group identified oncomodulin, other researchers—like Xi Gong He, PhD, here at Children’s, and Jeff Goldberg, MD, PhD, at Stanford—were also publishing their work on optic nerve regeneration. There was tremendous synergy in the field, with everyone’s work being very complementary.”
Three-pronged Approach has Synergistic Effect on Regeneration
The boom in optic nerve regenerative research led Dr. Benowitz to his next finding. He discovered that stimulating oncomodulin, increasing the levels of cyclic adenosine monophosphate, and deleting the gene that encodes the enzyme PTEN caused optic nerve fibers to grow the full length of the visual pathway and restored some basic elements of vision. While these results were promising, Dr. Benowitz wanted to know what was preventing the other cells from surviving and regenerating.
Zinc Inhibits Regeneration
Paul Rosenberg, MD, PhD, one of Benowitz’s colleagues at Boston Children’s Hospital, had been studying the role of zinc in the nervous system. “We found that ionic zinc levels were astonishingly elevated when the optic nerve was injured,” Dr. Benowitz said. His team also discovered that zinc chelation improved the survival of retina neurons and stimulated nerve fiber regeneration in mice.
Molecular Mechanisms of Regeneration
Dr. Benowitz and researchers from Stanford and the Scripps Institute are now digging into the molecular mechanisms of nerve regeneration. With funding from the National Eye Institute Audacious Goals Initiative, they aim to identify genes and proteins that help or hinder the ability of retinal ganglion cells to regenerate, grow axons to a target, and become functional in mice.
With grant support from the U.S. Department of Defense, Dr. Benowitz is also examining the earliest gene expression changes that are linked to regeneration, and evaluating the molecular differences between nerve cells that regenerate and those that do not.
Looking to the Future
“The next challenges are to optimize nerve regeneration and test whether it restores functionally meaningful levels of vision for patients with traumatic injuries and glaucoma.” This translational research holds promise for millions of patients worldwide with traumatic brain injuries and diseases, like glaucoma, that damage the optic nerve and cause permanent vision loss and blindness.